Carbon Chain Length Modulates MDA-MB-231 Breast Cancer Cell Killing Mechanisms by Mitochondrially Targeted Aryl?Urea Fatty Acids |
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Authors: | Prof Michael Murray Dr Ariane Roseblade Dr Yongjuan Chen Kirsi Bourget Dr Tristan Rawling |
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Affiliation: | 1. Discipline of Pharmacology School of Medical Sciences Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, 2006 Australia;2. School of Mathematical and Physical Sciences Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, 2007 Australia |
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Abstract: | Targeting the tumor cell mitochondrion could produce novel anticancer agents. We designed an aryl?urea fatty acid ( 1 g ; 16({4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid) that disrupted the mitochondrion and decreased MDA-MB-231 breast cancer cell viability. To optimize the aryl?ureas the present study evaluated mitochondrial targeting by 1 g analogues containing alkyl chains between 10–17 carbons. Using the dye JC-1, the C12?C17 analogues efficiently disrupted the mitochondrial membrane potential (IC50s 3.5±1.2 to 7.6±1.1 μM) and impaired ATP production; shorter analogues were less active. 7-Aminoactinomycin D/annexin V staining and flow cytometry showed that these agents activated the killing mechanisms of necrosis and apoptosis to varying extents (7-aminoactinomycin D/annexin V staining ratios 4.3–6.0). Indeed, 1 g and its C17 analogue preferentially activated necrosis and apoptosis, respectively (ratios 2.1 and 16). Taken together, alkyl chain length is a determinant of mitochondrial targeting by aryl?ureas and can be varied to develop analogues that activate apoptosis or necrosis in a regulated fashion. |
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Keywords: | antitumor agents apoptosis breast cancer fatty acids lipid drugs |
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